PepT1-/- microbiota therapy as a treatment for colitis

PepT1-/- 微生物群疗法作为结肠炎的治疗方法

• 批准号: 10655304
• 负责人: DIDIER MERLIN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655304
• 关键词: Adult; Affect; Alginates; Anti-Inflammatory Agents; Bacteria; Cell physiology; Cells; Colitis; Colon; Colorectal Cancer; Crohn' s disease; Data; Diagnosis; Down-Regulation; Drug Delivery Systems; Engraftment; Epithelial Cells; Etiology; Foundations; Funding; Future; General Population; Genetic; Goals; Healthcare; Hydrogels; Immune system; Inflammation; Inflammatory; Intestinal permeability; Intestines; Large Intestine; Mediating; Membrane Transport Proteins; Metabolic; MicroRNAs; Modification; Mucosal Immune Responses; Mucous body substance; Mus; Oligopeptides; Oral; Oral Administration; Oral Examination; Pathologic; Patients; Peptides; Phenotype; Population; Predisposition; Prevention; Proteomics; Protons; Research; Role; Severities; Small Intestines; Testing; United States National Center for Health Statistics; Up-Regulation; Variant; Veterans; Wild Type Mouse; cell type; cellular targeting; colitis associated cancer; dextran sulfate sodium induced colitis; experimental study; fecal transplantation; gain of function; genome-wide; gut inflammation; in vivo; intestinal epithelium; intestinal homeostasis; loss of function; member; metabolome; microbiota; microbiota transplantation; military veteran; mouse model; murine colitis; nanoparticle; novel; prevent; response; therapeutic development; tumorigenesis

PepT1, which is a member of the proton oligopeptide transporter (POT) superfamily, is well known to transport di/tripeptides. Our group and others have shown that PepT1 is highly expressed in epithelial cells of the small intestine, but present at low or undetectable levels in such cells of the normal large intestine. In addition, we have demonstrated that colonic PepT1 expression is up-regulated in colitis and colitis-associated cancer (CAC). By generating gain- and loss-of-function mouse models with PepT1 expression specifically in intestinal epithelial cells (IECs), we explored the role of PepT1 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis. We also examined the expression and transport activities of PepT1, using mouse models of colitis and CAC, and further revealed that the function of this membrane transporter is not restricted to its classical function as a transporter of di-tripeptides. For example, we demonstrated that PepT1 expression helps maintain intestinal homeostasis by mediating intestinal miRNA expression/secretion. Importantly we demonstrated during the last funding cycle that the PepT1-/- microbiota/metabolome is sufficient to protect against colitis and CAC. The overall goal of the current proposal is to develop a drug delivery platform to treat colitis. The initial aim of this proposal will be to investigate whether oral delivery of alginate hydrogel-loaded PepT1-/- microbiota will enhance the engraftment dynamics/diversity of the donor microbiota and consequently enhance the prevention/treatment of colitis. In the second aim, we will explore the cellular targets of PepT1-/- microbiota and assess the subsequent intestinal cellular responses that decrease colitis. Finally, we will characterize and assess the in vivo colitis-preventing effects of oral administration of specific anti-inflammatory metabolites from PepT1-/- microbiota loaded into nanoparticles. The proposed research will facilitate the development of therapeutic solutions targeting intestinal inflammatory and colitis associated cancer conditions.

PepT1是质子寡肽转运体(POT)超家族的成员之一，是众所周知的 转运二/三肽。我们的团队和其他人已经证明PepT1在血管内皮细胞中高表达。 小肠，但在正常大肠的这种细胞中存在低水平或检测不到的水平。在……里面 此外，我们还证明了在结肠炎和结肠炎相关疾病中，结肠PepT1的表达上调。 癌症(CAC)。通过生成具有PepT1表达的功能增强和功能丧失的小鼠模型 肠上皮细胞(IECS)，我们探讨了PepT1在肠道内稳态、炎症和 结肠炎相关肿瘤发生。我们还检测了PepT1的表达和转运活性 小鼠结肠炎和CAC模型，并进一步揭示了这种膜转运蛋白的功能不是 仅限于其作为二三肽转运体的经典功能。例如，我们演示了PepT1 通过调节肠道miRNA表达/分泌，miRNA的表达有助于维持肠道内环境的稳定。 重要的是，我们在上一个资助周期中证明了PepT1-/-微生物群/代谢组是足够的 预防结肠炎和CAC。目前提案的总体目标是开发一种药物递送 治疗结肠炎的平台。这项提案的最初目的将是调查口服藻酸盐 水凝胶负载PepT1-/-微生物区系将增强供体微生物区系的植入动力学/多样性 从而加强对结肠炎的预防/治疗。在第二个目标中，我们将探索细胞 PepT1-/-微生物区系的靶标，并评估随后减少结肠炎的肠道细胞反应。 最后，我们将表征和评估口服特定药物预防结肠炎的体内效果。 来自PepT1-/-微生物区系的抗炎代谢产物被装载到纳米颗粒中。拟议的研究将 促进针对肠炎和结肠炎的治疗解决方案的开发 癌症状况。

项目成果

Co-delivery of camptothecin and curcumin by cationic polymeric nanoparticles for synergistic colon cancer combination chemotherapy.

阳离子聚合物纳米颗粒共同递送喜树碱和姜黄素用于协同结肠癌联合化疗

• DOI: 10.1039/c5tb01245g
• 发表时间: 2015-10-21
• 期刊: Journal of materials chemistry. B
• 作者: Xiao B;Si X;Han MK;Viennois E;Zhang M;Merlin D
• 通讯作者: Merlin D

Edible ginger-derived nanoparticles: A novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer.

• DOI: 10.1016/j.biomaterials.2016.06.018
• 发表时间: 2016-09
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Zhang M;Viennois E;Prasad M;Zhang Y;Wang L;Zhang Z;Han MK;Xiao B;Xu C;Srinivasan S;Merlin D
• 通讯作者: Merlin D

PepT1 Expression Helps Maintain Intestinal Homeostasis by Mediating the Differential Expression of miRNAs along the Crypt-Villus Axis.

• DOI: 10.1038/srep27119
• 发表时间: 2016-06-01
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Zhang Y;Viennois E;Zhang M;Xiao B;Han MK;Walter L;Garg P;Merlin D
• 通讯作者: Merlin D

Inhibition of MDR1 gene expression and enhancing cellular uptake for effective colon cancer treatment using dual-surface-functionalized nanoparticles.

• DOI: 10.1016/j.biomaterials.2015.01.014
• 发表时间: 2015-04
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Xiao, Bo;Zhang, Mingzhen;Viennois, Emilie;Zhang, Yuchen;Wei, Na;Baker, Mark T.;Jung, Yunjin;Merlin, Didier
• 通讯作者: Merlin, Didier

Oral administration of pH-sensitive curcumin-loaded microparticles for ulcerative colitis therapy.

• DOI: 10.1016/j.colsurfb.2015.07.081
• 发表时间: 2015-11-01
• 期刊: Colloids and surfaces. B, Biointerfaces
• 作者: Xiao B;Si X;Zhang M;Merlin D
• 通讯作者: Merlin D